Many illnesses or conditions require administration of a constant or sustained level of a medicament or biologically active agent to provide the most effective prophylactic or therapeutic effect. This may be accomplished through a multiple dosing regimen or by employing a system that releases the medicament in a sustained fashion.
Systems for delivering sustained levels of medication have employed biodegradable materials, such as polymers, encapsulating the medicament. The use of biodegradable polymers, for example, in the form of microparticles or microcarriers, provides a sustained release of medicaments, by utilizing the inherent biodegradability of the polymer to control the release of the medicament thereby providing a more consistent, sustained level of medication and improved patient compliance.
Certain methods of fabricating polymer-based sustained release devices comprise the steps of dissolving a polymer in a solvent, adding to the polymer solution the active agent to be incorporated and removing the solvent from the mixture thereby forming a matrix of the polymer with the active agent distributed throughout the matrix.
Many of these methods of fabricating polymer-based sustained release devices employ a solvent or mixture of solvents, which solubilizes the polymer, but are not capable of solubilizing the active agent to be incorporated. Hence, these methods have disadvantages, for example, in the lack of suitable solvents which are capable of dissolving both active agent and polymer and which are non-toxic, biocompatible and can be readily removed from the final product; in solubilizing of the active agent in an active form; and in optimizing encapsulation efficiency of the active agent to achieve a device with the desired release characteristics.
Therefore, a need exists for improved methods for fabricating a polymer-based sustained release device, particularly devices having a high load of active agent.
The present invention is based upon the discovery that an improved polymer-based sustained release device can be achieved when a continuous phase which is capable of solubilizing both the polymer and the active agent is employed in the method for fabricating the device. Unexpectedly, an advantage of the sustained release devices obtained thereby is that they can have a very high load of active agent. For example, the device can achieve a relative weight of active agent in excess of the total polymer weight (e.g., present at about 50% by weight or more of the total weight of the device) with improved encapsulation efficiency and improved sustained release characteristics.
An additional advantage of the invention is that it allows for the preparation of small microparticles which contain encapsulated drug and exhibit improved delivery characteristics. A further advantage is the ability to use solubility properties of the active agent to affect particle size of the active agent, further enabling improved delivery characteristics. Additionally, the process for preparing microparticles may be improved by permitting the ability to filter sterilize process components or facilitate atomization of the polymer/active agent solution or dispersion.
The present invention thus relates to a polymer-based sustained release device, and methods of forming and using said device for the sustained release of an active agent. The improved method of the invention, for forming the polymer-based sustained release device, utilizes a continuous phase which comprises, for example, one or more polymer solvents, a polymer solvent/polymer non-solvent mixture or a polymer solvent/active agent non-solvent mixture, to dissolve the polymer and also solubilize the active agent in the polymer solution. Also embraced by the invention described herein is a process wherein the continuous phase comprises a polymer solvent/active agent non-solvent mixture and the active agent is present as a microparticulate. For purposes of the invention, the term xe2x80x9cmicroparticulatexe2x80x9d describes the situation where the active agent is dispersed in the continuous phase at a concentration of the active agent approaching solubilization of the active agent or where the active agent is present as a combination of both dispersed particulate and solubilized active agent. Typically, the microparticulate is formed by mixing an active agent non-solvent with a solution containing the active agent which thereby leads to partial or complete precipitation of the active agent (also referred to as the xe2x80x9cMicroparticulate Methodxe2x80x9d).
In one embodiment, the method comprises (a) forming a polymer/active agent solution by mixing a polymer, a continuous phase comprising one or more polymer solvents and an active agent wherein the polymer and active agent are present in relative concentrations such that the final product contains about 50% by weight or more of active agent; and (b) removing the continuous phase of step (a) thereby forming a solid polymer/active agent matrix.
The method can further comprise the step of forming droplets of the polymer/active agent solution prior to removal of the continuous phase. Further, the method can comprise freezing the droplets prior to removal of the continuous phase. According to the method of the invention the droplets can be microdroplets. In a specific embodiment wherein droplets are formed and then frozen, the continuous phase can be removed by an extraction process. Alternatively, the continuous phase can be removed by an evaporation process or a combination of an evaporation and extraction process.
When the continuous phase comprises one or more polymer solvents any combination of polymer solvents which is miscible and allows both the polymer and active agent to be dissolved, is suitable for use in the invention. Dimethylsulfoxide (also referred to as DMSO) is preferred because it is a good solvent for many polymers and active agents, including water-soluble agents such as peptides, antigens, and small molecule drugs. Other suitable solvents. in particular for PLGA polymers include, DMSO, ethyl acetate, methyl acetate, methylene chloride, chloroform, hexafluoroisopropanol, acetone, and combinations thereof. Preferably, the polymer solvent is pharmaceutically acceptable.
In another embodiment, the method for forming a polymer-based sustained release device comprises the steps of: (a) forming a polymer/active agent solution by mixing a polymer, an effective amount of an active agent and a continuous phase comprising a polymer solvent/polymer non-solvent mixture wherein the amount of polymer non-solvent is dictated by achieving solubilization of the active agent without causing substantial precipitation of the polymer; and (b) removing the continuous phase of step (a) from the polymer/active agent solution, thereby forming a solid polymer/active agent matrix. In a further embodiment, the active agent is present at a concentration such that the final product or device contains about 50% by weight or more of active agent.
The method can further comprise the step of forming droplets of the polymer/active agent solution prior to removal of the continuous phase. Further, the method can comprise freezing the droplets prior to removal of the continuous phase. According to the method of the invention the droplets can be microdroplets. In a specific embodiment wherein droplets are formed and then frozen, the continuous phase can be removed by an extraction process. Alternatively, the continuous phase can be removed by evaporation process or a combination of an evaporation and extraction process.
The polymer non-solvent can be selected such that it is miscible with the polymer solvent, does not cause substantial precipitation of the polymer and is not deleterious to the active agent. Preferably, the polymer solvent and the polymer non-solvent are pharmaceutically acceptable.
Suitable polymer non-solvents include, for example, ethanol, methanol, water, acetonitrile (MeCN), dimethylformamide (DMF), ethyl ether, alkanes such as pentane, isopentane, hexane, heptane and oils, such as mineral oils, fish oils, silicone oils, vegetable oils, or combinations thereof. Vegetable oils, such as olive oil, sesame oil, soybean oil, safflower oil, peanut oil, cottonseed oil, coconut oil, linseed oil, corn oil, castor oil, palm oil, or combinations thereof, are preferred for use in the invention. In particular embodiments, the polymer solvent is DMSO and the non-solvent is ethanol or water.
In another embodiment, the method for forming a polymer-based sustained release device comprises the steps of: (a) forming a polymer/active agent mixture by mixing a polymer, an effective amount of an active agent and a continuous phase comprising a polymer solvent/active agent non-solvent mixture wherein the amount of active agent non-solvent is dictated by achieving solubilization of the active agent, or alternatively achieving the active agent as a microparticulate in the continuous phase containing the polymer; and (b) removing the continuous phase of step (a) thereby forming a solid polymer/active agent matrix. In a further embodiment, the active agent is present at a concentration such that the final product or device contains about 50% by weight or more of active agent.
The method can further comprise the steps of forming droplets of the polymer/active agent solution prior to removal of the continuous phase. Further, the method can comprise freezing the droplets prior to removal of the continuous phase. According to the method of the invention the droplets can be microdroplets. In a specific embodiment wherein droplets are formed and then frozen, the continuous phase can be removed by an extraction process. Alternatively, the continuous phase can be removed by evaporation process or a combination of an evaporation and extraction process.
The active agent non-solvent can be selected such that it is miscible with the polymer solvent, does not substantially precipitate the polymer, and is not deleterious to the active agent. Suitable active agent non-solvents are dependent upon the properties of the active agent and for peptides can include, for example, acetone, ethanol and methylene chloride.
In another aspect, the invention relates to a polymer-based sustained release device prepared according to the method of the invention. The device comprises a polymeric matrix and an active agent dispersed within the matrix. The device formed by the method of the invention exhibits a unique microstructure, the porosity of which varies as a function of load, polymer concentration and the type of continuous phase employed.
The method of using the polymer-based sustained release device of the present invention comprises providing a sustained delivery of active agent, in a subject, over a therapeutically useful period of time, by administering to the subject a dose of said polymer-based sustained release device. The invention also provides methods for preparing microparticles of varying size and/or morphology for use in specific applications, for example, applications such as chemoembolization, vaccine delivery or cellular uptake where the size of the microparticles directly impacts performance.